天然产物Daptomycin作为首个临床应用的脂酰环肽酯类新型抗菌药物，其疗效独特，抗耐药好，但药源稀缺,价格昂贵。因其结构复杂，化学合成方法面临挑战。本项目拟在前期研究的基础上发展简便易行的全固相组合化学合成方法，对Daptomycin的结构进行序列多样化设计和结构改造，结合高通量筛选技术研究其抗菌的构效关系。研究结果将为发现新的先导药物提供多样化的分子样本，丰富和创新脂酰环肽酯类复杂天然产物的合成方法学。主要内容: (1)以Daptomycin的骨架结构为模板，采用不同环合位点以及保护与去保护策略，研究环合反应的选择性和高效性，优化Daptomycin及其类似物的固相全合成方法和简便路线。(2)采用全固相组合合成法对Daptomycin结构上的氨基酸进行序列数目变换和丙氨酸扫描取代，研究氨基酸的侧链和数目对环合产率及抗菌活性的影响规律。(3)优化影响脂酰环肽酯抗菌剂构效关系的关键基团。

Daptomycin from natural products, as the first clinically applied macrocyclic depsipeptide antibiotic, has a unique efficacy and rare cross-resistant bacteria. However, due to the scarcity of its natural sources and the challenges in synthesis, daptomycin is very expensive. The aim of this project is to develop a simple, total solid-phase method of chemically synthesizing daptomycin based on predecessing research, to make diverse designs and modifications of the structural sequence of daptomycin and to study its antimicrobial structure-activity relationship and molecular mechanisms,by using high through-put screening technology. The results will diversify and innovate the synthesis strategies for preparing complex macrocyclic depsipeptides, and will pave the way for discovering new drugs. The key points of this research:(1) By using daptomycin's ring skeleton as a template, we will study the strategies for selective protection and de-protection in a resin-based cyclic reaction of depsipeptides,establish and optimize a simple, total solid-phase synthesis method for new daptomycin rings. (2) The parallel syntheses of the alanine-scanning subsitutes of daptomycin will be conducted, and the effect the alanine side chain on the yield and antimicrobial activity of the daptomycin ring will be explored. (3) Re-combine the key amino acids on the daptomycin ring to study the antimicrobial structure-activity relationship and molecular mechanisms of daptomycin analogues.